Mutations in adenylosuccinate synthase 1 (ADSSL1) can cause myopathy, which is characterized by symptoms that typically begin in adolescence. These symptoms include primarily distal muscle involvement, mild facial muscle weakness, and a slight increase in serum creatine kinase (CK) levels. This form of distal myopathy was first identified in Korea through a study using exome sequencing conducted in 2015 [1]. Globally, there are fewer than 200 known cases [2].

Distal myopathies represent a diverse group of rare, progressive hereditary muscle disorders that predominantly affect the muscles of the distal limbs [1]. To date, researchers have identified more than 16 genes responsible for distal myopathy, with the majority linked to autosomal dominant (AD) inheritance patterns [1]. Recently, the ADSSL1 gene has been implicated in this condition. ADSSL1 encodes the muscle-specific enzyme adenylosuccinate synthetase like 1, which is crucial for purine nucleotide interconversion. This enzyme catalyzes the initial step in the de novo synthesis of adenosine [3].

Here, we describe a case of ADSSL1 mutagenic myopathy that was misdiagnosed and initially treated as Becker muscular dystrophy (BMD). Furthermore, we discuss the importance of re-evaluating diseases that deviate from the typical clinical course of traditional myopathies, in light of recent advances in diagnostic techniques.

A 39-year-old man presented at the Department of Rehabilitation Medicine for an evaluation of progressive symptoms, which included balance issues during standing and walking, as well as weakness in the distal extremities. At the age of 20, he sought treatment at another tertiary hospital for facial weakness and poor physical performance, notably difficulty in running. He had no issues with swallowing, pulmonary function, or cardiac health. A physical examination, conducted using the Medical Research Council (MRC) score, revealed a muscle strength grade of approximately 3 to 4 in both the upper and lower extremities.

Laboratory findings from 2002 indicated hyperCKemia, with a CK level of 1,707 IU/L (reference range, 0 to 170). A muscle biopsy was conducted, and hematoxylin-eosin staining showed increased nuclei internalization, hypertrophic fibers, degenerating fibers, myophagocytosis, and fiber splitting. Immunohistochemistry revealed dystrophin expression along the sarcolemma. The dystrophin gene deletion test showed no exon deletions. Due to the limitations of genetic testing at the time, it was not possible to identify other genetic disorders that could present with these muscular symptoms. The presence of dystrophin, distinguishing the condition from Duchenne type, led to a presumptive diagnosis of BMD [4]. In his late 20s, as his symptoms worsened, including difficulties in grasping and pinching with his hands, he found it challenging to perform everyday activities.

At the time of the patient’s visit to our hospital, his cognitive function and other medical conditions remained unchanged. Bilateral shoulder abduction, elbow flexion, and wrist extension had a score of 3/3; bilateral finger flexion and extension scored 2/2; bilateral hip flexion and knee extension had a score of 3/3; and bilateral ankle dorsiflexion and plantar flexion scored 2/2, according to the MRC scale. The deep tendon reflexes in the bilateral ankle jerks were hypoactive. He continued to have no issues with swallowing, pulmonary function, or cardiac health, and his family history was unremarkable (Fig. 1).

Despite the initial diagnosis, the clinical course and current neurological state suggested that a presumptive diagnosis of BMD was regarded as inappropriate. The primarily affected muscles exhibited distal differences, which contrasted with the typical manifestations of BMD. Consequently, we conducted nerve conduction studies and electromyography (EMG), including quantitative EMG. The nerve conduction study was normal, except for a reduced amplitude of the compound motor action potential in the bilateral extensor digitorum brevis muscles (Tables 1, 2). The EMG findings indicated myopathic patterns predominantly in the distal limbs (Tables 1, 2, Fig. 2).

Based on the patient's family history, facial weakness, prominent distal muscle atrophy, and the identification of myopathic patterns in the distal muscles on EMG, which were compatible with distal myopathy, we requested genetic testing. Diagnostic exome sequencing revealed pathogenic variants of ADSSL1—specifically. c.910G>A and c.1048 del mutations, with minor allele frequencies of 0.0034% and 0.0081%, respectively, in the human population (Table 3). In light of the diagnosis of ADSSL1 mutagenic myopathy, we provided genetic counseling for myopathy of autosomal recessive (AR) inheritance, which is different from AD or sex-linked inheritance.

The requirement for written informed consent was waived because it was impractical to obtain, refusal was unlikely, and the risk to research subjects was extremely low. The study received approval from the Institutional Review Board of Konyang University Hospital (IRB no: 2023-03-004-004).

Distal myopathy is a genetic disorder characterized by the progressive loss of muscle tissue. In contrast to proximal dystrophies, which mainly involve defects in sarcolemmal proteins, distal muscular dystrophies are most often caused by mutations in genes that encode sarcomeric proteins [5]. It remains unclear why these specific genetic defects predominantly affect distal muscles. These mutations alter the structural and functional integrity of the sarcomere [5]. Further research is essential to investigate potential therapeutic strategies.

ADSSL1 mutagenic myopathy is an AR distal myopathy, predominantly reported in Asians [6], with an estimated prevalence of less than 0.1 per 1,000,000 population and a currently reported number of cases ranging between 100 and 200 [2]. ADSSL1, which is located on chromosome 14q32.33, encodes the ADSSL1 protein, a muscle-specific enzyme crucial for energy metabolism in skeletal muscles, particularly in the muscle and heart [7]. Defects in ADSSL1 disrupt the purine nucleotide cycle, interfering with normal muscle function and leading to progressive muscle weakness and myopathy. Similar to other metabolic and mitochondrial diseases affecting the muscular system, the severity and progression of the disease vary among patients. However, it typically presents in adolescence during periods of rapid growth, when structural stress from stretching across growing bones and demands on protein synthesis and cellular energy are at their peak [2]. From the standpoint of physiatrists, there is a need for more accuracy regarding the methods, intensity, and frequency of rehabilitation therapy for patients with distal myopathy.

Before the widespread adoption of genetic testing in diagnostics, primary tools for diagnosing muscular diseases included blood tests, EMG, and biopsies. These methods helped identify affected areas and differentiate between various myopathies, such as inflammatory myopathy. To diagnose ADSSL1 mutations, exome sequencing is essential. However, until recently, challenges in genetic testing have led to reports of muscular diseases being misdiagnosed as BMD in cases diagnosed several years ago [8,9].

Previous studies have indicated that both muscle biopsy and EMG are viable methods for diagnosing neuromuscular diseases. EMG, which is widely accessible, provides advanced quantitative assessments, boasts higher sensitivity, and can be applied to various affected areas. However, its major limitation is that it lacks specificity and offers no insights into pathogenesis. In contrast, muscle biopsy, particularly with the advent of electron microscopy, has become highly sensitive but remains significantly invasive [10]. The recent surge in genetic testing has lessened the reliance on these invasive biopsies, which are not only costly but also time-consuming. Nonetheless, the implementation of genetic testing requires careful consideration of both ethical issues and expenses.

An incorrect diagnosis can delay appropriate treatment and potentially cause fatal harm to patients. It is crucial to raise awareness about conditions that are frequently misdiagnosed. Previous studies have shown that patients with myopathy, who were misdiagnosed with BMD, did not undergo genetic or EMG testing at the time of their diagnosis [8,9]. Clinical courses and subsequent reevaluations, which included genetic and EMG testing, have led to the identification of new genetic diseases [8,9]. Therefore, a meticulous evaluation that includes comprehensive history taking, physical examinations, EMG, and genetic testing is beneficial for accurate long-term diagnoses of genetic disorders.

As for ADSSL1 mutagenic myopathy, effective treatments have yet to be developed. This underscores the necessity for future research, similar to other genetic diseases where treatments are still not established.

In conclusion, accurate diagnoses are essential for managing progressive diseases, such as neuromuscular disorders, to effectively guide treatment and rehabilitation strategies. This case underscores the significance of an accurate diagnosis by correcting an initial presumptive diagnosis of BMD through EMG and genetic testing, thereby reinforcing the diagnostic utility of EMG for future applications.

We provided rehabilitative treatment focused on the distal muscles to enhance daily functioning and to educate patients about their condition and the associated inheritance risks. Periodic reassessment of long-term conditions, especially genetic diseases, helps differentiate similar conditions, improve patient education, refine treatment planning, and enhance overall future quality of life.